Bis(aminoalkylsulfamoyl) anthraquinones

ABSTRACT

D R A W I N G

United States intent [72] Johann Grisar;

Arthur D. Sill; Robert W. Fleming, all oi Cincinnati, Ohio I 777,885

Nov. 21, 1968 Dec. 14, 197 l Richardson-Merrell Inc.

New York, N.Y.

inventors Appi. No. Filed Patented Assignee BIS(AMINOA'LKYLSULFAMOYL) ANTHRAQUINON ES 7 Claims, No Drawings US. Cl

Int. Cl

Field 01' Search References Cited UNITED STATES PATENTS 3/1945 Kienle et a1 OTHER REFERENCES Feldman et 211., as cited in Chem. Abstracts, 59, 11312,

Primary Examiner-Lorraine A. Weinberger Assistant Examiner-E. Jane Skelly Attorney-Harvey W. Edelbiute ABSTRACT: A compound selected from a base of the mu a V Formula I BIS(AMINOALKYLSULFAMOYL) ANTHRAQUHNONES This invention relates to'novel anthraquinone compounds. More particularly this invention relates to certain novel bis(dialkylaminoalkylsulfamoyl)anthraquinone bases, pharmaceutically acceptable acid addition salts of such bases, their method of preparation and use.

It can be seen from the above generic formula 1 that R, can be hydrogen or methyl. Preferably R, is hydrogen. Each of R and R is a saturated or unsaturated alkyl group having three to five carbon atoms, e.g., propyl, butyl, amyl, isoamyl or allyl. Preferably each-of R and R is butyl. The unsaturated alkyl is also referred to herein as alkenyl. The designator (n) is an integer of 2 to 4 so that the (-CH group is 1,2-ethylene, 1,3-propylene or 1,4-butylene. Preferably (n) is 3 so that the alkylene group is 1,3-propylene. The two dialkylaminoalkylsulfamoyl or dialkenylaminoalkylsulfamoyl substituents can be attached, one to each benzene ring of the anthraquinone moiety, at any positions, preferably at the 2,6- or 2,7-positions, respectively, that is, in mor p-position in respect to the I two carbonyl functions. The various (n), R, R and R groups can be the same or different for each compound. Preferably, each (n) is the same, each R is the same and both the R groups and R groups are the same for any particular compound.

The closest prior art compound known to applicants is 1,5- bis[N-( 4-diethylaminol -methylbutyl)sulfamoyl]anthraquinone. The preparation of this compound is disclosed in l. Kh. Feldman, Z. Ovsyanaya, and E. Kozlov, Tr. Leningr. Khim.- Farmatsevt. Inst. 1960 (11), 48-53; ca. 59: 11312. However, applicants prepared and tested this compound and found that it is very much more toxic than the compounds of this invention. Furthermore, this compound was found to be inactive in antiviral tests used with the compounds of this invention.

Salts of the base compounds of this invention are primarily pharmaceutically acceptable acid addition salts with inorganic or organic acids. Suitable inorganic acids are, for example, mineral acids, such as hydrohalic acids, e.g., hydrochloric or hydrobromic acid, or sulfuric or phosphoric acids. Organic acids are, for example, lower aliphatic hydrocarbon monocarboxylic acids, e.g., glycolic or lactic acid and the like, lower aliphatic lower alkoxy-hydrocarbon monocarboxylic acids, e.g., methoxy-acetic orethoxy-acetic acids and the like, lower aliphatic lower alkanoyl-hydrocarbon monocarboxylic acids, e.g., pyruvic acid and the like, lower aliphatic hydrocarbon dicarboxylic acids, e.g., oxalic, malonic, succinic, methylsuccinic, dimethylsuccinic, glutaric, a-methylglutaric, B-methylglutaric, itaconic, ma leic, citraconic, homocitraconic, or fumaric acid and the like, lower aliphatic hydroxy-hydrocarbon dicarboxylic acids, e.g., malic or tartaric acid and the like, lower aliphatic lower alkoxy-hydrocarbon dicarboxylic acids, e.g., a,B-dimethoxysuccinic or ethoxymaleic acid and the like, lower aliphatic hydrocarbon tricarboxylic acids, e.g., aconitic or tricarballylic acid and the like, lower aliphatic hydroxyhydrocarbon tricarboxylic acids, e.g., citric acid and the like. Furthermore, organic sulfonic acids, such as lower alkane sulfonic acids, e.g., methane sulfonic or ethane sulfonic acid and the like, or lower hydroxy-alkane sulfonic acids, e.g., 2- hydroxy-ethane sulfonic acid and the like, may be suitable. Particularly useful are pharmacologically acceptable acid addition salts with mineral acids, e.g., hydrochloric acid. Monoor diacid salts may be formed; also, the salts can be hydrated, e.g., monohydrate, or substantially anhydrous.

The compounds of this invention can be administered to animals, e.g., warmblooded animals, for their prophylactic and/or therapeutic antiviral effects by conventional modes of administration, either alone but preferably with pharmaceutical carriers. lllustratively, administration can be parenterally e.g., subcutaneously or intramuscularly, topically, e.g., intranasally or intravaginally, or orally.

The dosage administered will be dependent upon the virus for which treatment or prophylaxis is desired, the type of animal involved, and similar considerations. Generally, a daily dosage of the active ingredient can be from less than about 0.02 or over 500 mg. (milligram) per kg. (kilogram) of body weight and preferably from about 0.1 to about 50 mg./kg. of body weight. The novel compounds together with conventional pharmaceutical carriers can be employed in unit dosage forms such as solids, for example, tablets or capsules, or liquid solutions, suspensions, or elixirs for oral administration and ingestion or liquid solutions, suspensions, emulsions and the like for parenteral use. The quantity of active ingredient in each dosage will generally differ depending on the type of unit dosage, the type of animal and its weight. Thus, each dosage can contain from less than about 0.1 mg. to over 250 mg. of active ingredient in a significant quantity of pharmaceutical carrier.

The compounds of this invention can be used as antiviral agents for inhibiting or preventing a variety of viral diseases or infections. lllustratively, the compounds can be used for their antiviral effect against diseases caused or associated with picornavirus types, myxoviruses, arboviruses, poxviruses, and the like. When administered prophylactically, it is preferred that the administration of the compound be within 24 or 48 hours prior to invasion of the animal with pathogenic virus. When administered therapeutically, it is preferred that the administration be within about 24 or 48 hours after invasion with pathogenic virus. Preferably, these compounds are administered to the animal both prior, i.e., prophylactically, and after invasion, i.e., therapeutically, of the animal with a pathogenic virus, e.g., by administration of the compound on the day of invasion as metal as for a day or two prior to invasion and a day or two after such invasion.

The compounds of this invention have a tendency to degrade or react in contact with metals, e.g., galvanized steel. Therefore, it is preferred that metals which come in contact with these compounds be resistant to corrosion. A metal which can be used in contact with these compounds is stainless steel. J

A preferred mode of administration for the compounds (active ingredients) of this invention is parenterally such as by normally liquid injectable compositions, e.g., for intramuscular or subcutaneous administration. In such compositions the quantity of active ingredient can vary from about 0.05 to 20 percent by weight of the composition and preferably from about 0.1 to. 10 percent by weight. In order to minimize or eliminate irritation at the site of injection, the parenteral compositions can contain a nonionic surfactant such as those having an HLB (hydrophile-lipophile) balance) of about 12 to 17. Such formulations can be solutions, suspensions or emulsions in conventional liquid pharmaceutical carriers, e.g., sterile liquids such as water, saline, and aqueous dextrose (glucose) and related sugar solutions. The quantity of surfactant in the formulation can vary from about 5 to 15 percent by weight of the formulation. The quantity of a compound of this invention, either in the base form or a pharmaceutically acceptable acid addition salt in such formulations, can vary over a broad range such as that mentioned hereinbefore, i.e., 0.05 to 20 percent by weight of the formulation. Preferably, the active ingredient is in the base form. The remaining component or components of such formulations can be a normally liquid pharmaceutical carrier, e.g., isotonic aqueous saline, either alone or together with conventional excipients for injectable compositions. The surfactant can be a single surfactant having the above indicated l-lLB or a mixture of two or more surfactants wherein such mixture has the indicated HLB. The following surfactants are illustrative of those which can be used in such formulations: (A) Polyoxyethylene derivatives of sorbitan fatty acid esters, such as the Tween series of surfactants, e.g., Tween 80, and the like. The Tweens are manufactured by Atlas Powder Company. (B) High molecular weight adducts of ethylene oxide with a hydrophobic base formed by the condensation of propylene oxide with propylene glycol, e.g., Pluronic F-68 which is manufactured by Wyandotte Chemical Company. The preferred surfactant is Polysorbate 80, U.S.P., a polyoxyethylene sorbitan monooleate.

The compounds of the present invention can be prepared by reaction of an anthraquinonedisulfonyl (lower) alkyl ester or wherein Y is a halide or (lower) alkoxy and R, R, R and (n) have the same meaning as in formula 1.

The product can be isolated in some cases directly from the reaction mixture and purified by recrystallization. in other cases, the product was isolated as the free base after removal of excess starting material by appropriate washes.

Alternatively, the compounds of this invention may be prepared by alkylation of the Na, K or Li derivatives of N,N'- dimethyl anthraquinonedisulfonamides with dialkylaminoah kyl halides, or the N,N'-bis(dialkylaminoalkyl)anthraquino nesulfonamides may be alkylated with methylating agents such as methyl halide or a reactive ester of methanol such as methyl sulfate or methyl p-toluenesulfonate.

The anthraquinonedisulfonyl chloride intermediates can be prepared from the disulfonic acids or their salts by a variety of procedures well known to the art and described in detail by H. E. Fierz-David in Helvetica Chimica Acta, Volume 10, pages 197 to 227 (1927).

The following examples are illustrative of the invention.

EXAMPLE 1 Preparation of 2,6-bis-[N-( 3-Dibutylaminopropyl)Sulfamoyl] Anthraquinone Dihydrochloride To a suspension of 40.5 grams (0.1 mole) of anthraquinone- 2,6-disulfonyl chloride in 500 ml. of dry methylene chloride was added dropwise over 3 hours a solution of 46.6 g. (0.25 mole) of 3-dibutylaminopropylamine in 250 ml. of methyene chloride, and the mixture was stirred overnight at room temperature. The resulting precipitate was collected, washed with methylene chloride and recrystallized twice from a mixture of methanol and butanone adjusted, by boiling ofi methanol, to a proportion of the two solvents most conducive to crystallization. The product, m.p. l85-186, was obtained in a yield, after recovery of a second crop, of 75 percent.

EXAMPLE 2 Preparation of other 2,6-bis-[N-( Dialkylarninoalkyl )SulfamoyH-Anthraquinone Compounds Using the procedure described in example 1, additional 2,6- [N-(dialkylaminoalkyl)sulfarnoyl]anthraquinone derivatives were prepared. The base form of such compounds is shown by the following formula wherein the designator Ais described in the below table I.

st y limalelssalt ,7

EXAMPLE 3 Preparation of 2,7-bis-[N-( B-Dibutylaminopropyl)Sulfamoyl] --Anthraquinone Following the procedure of example 1 and using anthraquinone-ZJ-disulfonyl chloride, the title compound was obtained. Since the dihydrochloride was hygroscopic, it was converted to the free base by stirring it in a 10 percent sodium carbonate solution and recrystallized from a mixture of ether and hexane, m.p. 93-95.

EXAMPLE 4 EXAMPLE 5 Preparation of 2,6-bis-[N-( 3-Dibutylaminopropyl)-N-MethylsulfamoyllAnthraquinone I Following the procedure of example 1 and using N-methyl- N,N'-dibutylpropylenediamine, the title compound can be prepared.

Examples 6 to 22 illustrate in vivo antiviral studies with compounds, also referred to as active ingredients, of this invention. in each of the examples, the compounds were antivirally active. in examples 7-22, the compounds showed antiviral activity by prolonging the mean day of death of the treated animals as compared to the control animals, during the period of observation. in example 6, antiviral activity was shown by fewer lesions for the treated animals as compared to the controls, during the period of observation. The dosage levels of the compounds used in the examples were within the range of 2 to 50 mg. per kg. of animal body weight for each time the compound was administered.

Table A lists the active ingredient which was administered in each of the examples. Although it is believed that the headings in the examples are selfexplanatory, some of the headings are explained as follows: The challenge," i.e., inoculation with a virus, used is generally fatal to all the untreated, i.e., control, animals in the experiment. time of death refers to the average time of death for the untreated animals. The "treatment was prophylactic or therapeutic or both. The term volume" refers to the volume of composition administered per dose which contained the active ingredient dissolved in sterile water which also contained 0.15 percent of hydroxyethylcellulose. The control animals received a sham dosage of the same volume of the vehicle which did not contain the active ingredient.

anthrnquinone diacid maleate 9 lo l4 2,6-Bis-lS-dibulylnmlnopropyl)rulfamoyl]- l9 2,6-Bis-lN-(2-dibutylamino'ethyi)aulfamoyilanthmquinone dihydrochloride emhmquinone I 5 l.ll-Bil-[N-( B-dibulyllminopropyl )sulfamoyl 20 2.641254 N-(S dinllyluminopropylhulfamoyl umhraquinone dihydrochluride anlhraquinone diacid muleal: l6 I,S-Bia-lN-(B-dibutylunlnopropyl)aulfamoyl1- 2| x -i -(3- p py v py y ianthraquinone unthraquinone dihydrochloride l7 1.6-511-1 N-( J-dIbuIyhminopropyl)lulf l1. 22 2.6 -Bia [N-( J-dipcnlylaminoprupyl)aulfamoyl amhnquinone diuid maleau: amhraquinoric dihydrochloridc I 8 2,6-Bi|-[N-( 3-dltlopenlylnminoproyl)-|ulfamoyl]- lnthraqulnone dlhydrochlorlde Examples 7 8 Virus Vaccinia IHD Encephalomyocarditis. Encephalomyocarditis.

DNA, Poxvirus.. RNA, Picornavirus'...... RNA, Picornavirus.

24 ID50 0111350 15 LD Subcutaneous in taiL. Subcutaneous subcut 5 days days. 10 days Mice"... Mice 1g 12-15 grams. 12-15 grams Treated grou 10. Control group 0 40.

nd therapeutic Prophylactic and therapeutic Prophylactic and therapeutic. Route Subcutaneous Subcutaneous Subcutaneous. Volume 0.25 ml 0.25 ml 0.25 ml. Time:

Pro-challenge 28, 22, 4 hrs 28, 22, 4 hrs 28, 22, 4 hrs. Post-challenge 2, 20, 26 hrs 2, 20, 26 hrs 2, 20, 26 hrs.

1 Tall lesion scored on 7th qey. "W

Example 9 10 11 12 Virus Encephalomyocarditis.... Influenza AO(PRB) In(fi1 1enza )A/Equine Mango.

rague RNA, Picornavius- RNA, Myxovirus.--...... RNA, Myxovirus... RNA, Picornavirus.

LDm --L 16 LD50 68 LDsu 10 LD50. Subcutaneous Intranasal Intranesal Subcutaneous.

d 5days.-. fidays.

10 days. 10 days. Mice...- Mice. 12-15 grams 12-15 grams. Treated group 10. Control group-.-.. 29 5 20. Treatment Prophylactic and Prophylactic and Prophylactic and Prophylactic and therapeutic. therapeutic. therapeutic. therapeutic. Route. Subcutaneous Intraperitoneal Subcutaneous Subcutaneous. Volume 0.25 ml 0.25 ml 0.25 ml 0.25 ml. Time:

Pro-challenge 28, 22, 4 hrs 1 hr 28, 22, 4 hrs- 28, 22, 4 hrs. Post-challenge. 2, 20, 26 hrs 3, 6, 24, 27 hrs 2, 20, 26 hrs.. 2, 20, 26 hrs.

Example 13 14 15 16 Virus Semliki Forest Vaccinia IHD Encephalomyocarditis Encephalomyocarditis.

RNA, Arbovirus DNA, Poxvirus. RNA, Picornavims RNA, Picornavirus. 1 LD 240 I l6 LD Subcutaneous.

5 days. 10 days. Mice. g 1215 grams Treated group. Control group 20 20 10 30. Treatment Prophylactic and Prophylact c and Prophylactic and Prophylactic and therapeutic. therapeutic. therapeutic. therapeutic. Route Subcutaneous Subcutaneous Subcutaneous Subcutaneous. Volume 0.25 ml 0 ml 0.25 ml 0.25 ml. Time:

Pre-challenge. 28, 22, 4 hrs 28, 22, 4 hrs 28, 22, 4 hrs 28, 22, 4 hrs. Post-challenge 2, 20, 26 hrs 2, 20, 26 hrs 2, 20, 26 hrs 2, 20, 26 hrs.

1 Tail lesion scored on 7th day. w H W in" y Example 17 18 19 Virus Encephalomyocatditis Encephalomyocarditis Encephalomyocarditis- YP RNA, Picornavirus... RNA, Picornavirus. RNA, Picornavlrus. Ghallenge.. D 13 LDm 13 LDm- Subcutaneous. Subcutaneous. Timeoldeath 5 ays 5days Period of observation- 10 days 0 days A mal e Mice.

Weight. 12-15 grams- 12-15 grams. Treated group. r Control group. 30 30 20. Treatment.. Prophylactic and therapeutic. Prophylactic and therapeutic- Prophylactic and t e al u fi- Route. Subcutaneous... Subcutaneous Subcutaneous. Volume 0.25 ml 0.25 ml 0.25 ml. Time:

Pre-cha1lenge. 28, 22, 4 hrs 28, 22, 4 hrs 28, 22, 2 hrs. Post-challenge 2, 20, 26 hrs 2, 20, 26 hrs 2, 20, 26 hrs.

Example 20 21 22 Virus. Encephalomyocarditis Encephalomyocarditis Encephfil01fl0 YP RNA, Picornavlrus RNA, Picornavirus RNA, Ptcornavtrus. Challen 13 LDw 10 LDs 10 LDau- Route. Subcutaneous Subcutaneous Subcutaneous. Time of death 5 days. 5 days 5 y Period oi observ io J days ll days. 9 days. nimal Mi nn, M1cn ice.

Weight 12-15 grams- 12-15 grams 12-45 grams Treated group. 10 o n 10. Control group 20 10 20. Treatment Prophylactic and therapeutic. Prophylactic and thcrapoutlc Prophylactic and therapeutic.

O -l e. Subcutaneous... Subcutaneous Subcu Volume 0.25 ml 0.25 ml 0.25 ml. Time:

Put-challenge 28, 22, 2 hrs 2s, 22, 2 hrs 28, 22, 2 hrs- Post-challenge 2, 20, 26 hrs 2, 20, 26 hrs 2, 20, 26 hrs.

EXAMPLE 23 ture; and then autoclaving it for 20 minutes at 1 10 C. at p.s.i.g. steam pressure. The composition can be dispensed in a f 3 fi z i'l for a parental? m-leculon t single ampul for multiple dosage or in 10 or ampuls for sin- 9 owing w ereln e quantities are on a weight to vo time agle dosagem SIS. 20 What is claimed is:

1. A compound selected from a base of the formula: (a) 2,6-Bis-[N-(J-dibutylaminopropyl)sulfamoyl1- anthraquinone dihydrochloridc 100 mg. 0 (b) Sodium chloride I q.s. (c) Water for injection to make 10 ml. 1 R1 0 0 R2 2s l u n N(CH2)nN|S I S 'N (CH2)u' N The composition is prepared by dissolving the active inll gredient and sufiicient sodium chloride in water for injection Ra 0 R3 to render the solution isotonic. The composition may be dispensed in a single ampul containing 100 mg. of the active 30 h.

ingredient for multiple dosage or m 10 ampuls for single A. each Rrishydrogen or methyl;

dosage- B. each (n) is an integer of 2 to 4;

C. each of R and R is alkyl of three to five carbon atoms or EXAMPLE 24 alkenyl of three to five carbon atoms; or a pharmaceuti- An illustrative composition for a parenteral injection is the cally acceptable acid addition salt of said base. following aqueous emulsion. 2. A compound of claim 1 wherein each (n) is 3 and each R is hydrogen.

3. 2,6-bis-[ N-( B-dibutylaminopropyl )sulfamoyl Ech m" mmmm anthraquinone or a pharmaceutically acceptable acid addition contain: Ingredient Amount salt thereof- 4. 2,7-bis-[N-(3-dibutylaminopropyl)sulfamoyl1- 2.5 2,6-Bh-[N-(3-dlbutyl- 0.050 anthraquinone or a pharmaceutically acceptable acid addition angioprolpylhulhmoyil salt thereof. 5. 2,6-bis-[N-(3-diisopentylaminopropyl)sulfamoyll- 383;, ms 52:32: 2, am :2 anthraquinone or a pharmaceutically acceptable acid addition Wnter for injection, q.|. 20.000 ml. salt thereof.

6. 2,6-bis-[N-( 3-diallylaminopropyl)sulfamoyl l-anthraquin- The composition of example 24 is prepared by: dissolving 0.64 one or a pharrnaceutically acceptable acid addition salt grams of sodium chloride in 100 ml. of water for injection; thereof.

mixing the Polysorbate 80 with the active ingredient; adding a 7. l,8-bis-[N-(3-dibutylaminopropyl)sulfamoyl1- sufficient solution of the sodium chloride in water to the active anthraquinone or a pharmaceutically acceptable acid addition ingredient and Polysorbate to make 20 ml.; shaking the mixsalt thereof.

i i '4 III "I 

2. A compound of claim 1 wherein each (n) is 3 and each R1 is hydrogen.
 3. 2,6-bis-(N-(3-dibutylaminopropyl)sulfamoyl) -anthraquinone or a pharmaceutically acceptable acid addition salt thereof.
 4. 2,7-bis-(N-(3-dibutylaminopropyl)sulfamoyl) -anthraquinone or a pharmaceutically acceptable acid addition salt thereof.
 5. 2,6-bis-(N-(3-diisopentylaminopropyl)sulfamoyl) -anthraquinone or a pharmaceutically acceptable acid addition salt thereof.
 6. 2,6-bis-(N-(3-diallylaminopropyl)sulfamoyl) -anthraquinone or a pharmaceutically acceptable acid addition salt thereof.
 7. 1,8-bis-(N-(3-dibutylaminopropyl)sulfamoyl) -anthraquinone or a phaRmaceutically acceptable acid addition salt thereof. 